Project Summary Aging often leads to a functional decline across multiple cognitive domains, and there is a signficantly increased risk of depression and anxiety disorders in the aged. However, the physiologic and anatomic changes underlying these impairments are not fully understood. A number of changes in hippocampal structure and connectivity are associated with aging including a decline in neurogenesis in the subgranular zone of the dentate gyrus (DG) and decreased performance on hippocampus-dependent tasks. Levels of bone morphogenetic protein 4 (BMP4) in the mouse DG increase more than 10-fold between 8 and 52 weeks of age. A similar aging- related increase in BMP4 expression is found in the human DG. Conversely, levels of the BMP inhibitor, noggin, in the mouse DG decrease by about 70% during this time. This results in an extraordinary 30-fold aging-related increase in BMP signaling in the DG measured by levels of phosph-SMAD1/5/8. Reducing BMP signaling in aged mice by either intraventricular infusion or transgenic overexpression of noggin reverses aging-related changes in both neurogenesis and cognition, and it reduces depression-like behavior. Conversely, transgenic overexpression or intraventricular infusion of BMP4 in aged mice prevents the beneficial effects of exercise on neurogenesis and on cognitive and affective behavior. These findings lead to the hypothesis that changes in BMP signaling underlie the decreases in neurogenesis and in hippocampus- dependent behavior associated with aging. To test this hypothesis, we will first investigate the cellular and behavioral effects of inducible cre-mediated ablation of BMPRII in neural stem cells in the DG of aged mice. We then will examine the potential causal relationship between changes in neurogenesis and behavior. To begin to develop a potential therapeutic approach, we will use a new technology, spherical nucleic acid nanoparticle conjugates (SNAs), as an RNAi-based therapeutic approach to enable us to specifically target BMPR signaling in the brain to enhance adult neurogenesis. Finally, we will define changes in expression and cellular origin of BMP ligands, receptors, and inhibitors in the hippocampus of aging humans and examine correlations between BMP levels, neurogenesis, and age-associated cognitive decline in humans. The goal of the studies is to identify specific molecular loci where therapeutic intervention in the aged nervous system may lead to a return to normal neurological function.